This invention relates to detection and diagnosis of disease in human subjects. More particularly, this invention relates to molecular diagnosis of the autosomal dominant disorder Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and to detection of the chromosomal deletion at the HNPP locus.
HNPP is an autosomal dominant disorder that causes episodes of focal demyelinating neuropathy following minor trauma to peripheral nerves. HNPP, also called familial recurrent polyneuropathy, tomaculous neuropathy, and McKusick Number 162500, typically has an onset during adolescence and may cause attacks of pain, muscular weakness, and atrophy. J. De Jong, 50 Psychiatr. Neurol. Bull. 60 (1947); D. Davies, 2 Lancet 266 (1954); C. Earl et al., 33 Quart. J. Med. 481 (1964); A. Staal et al., 15 Neurology 1008 (1965); A. Windebank, Inherited Recurrent Focal Neuropathies, Peripheral Neuropathy 1137-48 (3d ed. 1992).
Carpal tunnel syndrome and other entrapment neuropathies are frequent manifestations of this disorder. Motor and sensory nerve conduction velocities are sometimes mildly reduced in clinically affected patients and in asymptomatic gene carriers. P. Dyck et al., 10 Ann. Neurol. 222 (1981). Pathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or sausage-like formations. F. Behse et al., 95 Brain 777 (1972); W. Bradley et al., 98 Brain 381 (1975); R. Madrid & W. Bradley, 25 J. Neurol. Sci. 415 (1975); J. Debruyne et al., 47 J. Neurol. Sci. 385 (1980).
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy in humans. Most patient pedigrees demonstrate an autosomal dominant Mendelian segregation pattern, although autosomal recessive and X-linked forms of CMT have been reported. For example, CMT loci have been mapped to chromosome 1 (CMT1B), T. Bird et al., 34 Am. J. Hum. Genet. 388 (1982), chromosome 17 (CMT1A), J. Vance et al., 104 Exp. Neurol. 186 (1989); J. Vance et al., 9 Genomics 623 (1991), another undetermined autosome (CMT1C), P. Chance et al., 47 Am. J. Hum. Genet. 915 (1990); P. Chance et al., 42 Neurology 2037 (1992), and the X chromosome, A. Gal. et al., 70 Hum. Genet. 38 (1985); K. Fishbeck et al., 20 Ann. Neurol. 527 (1986). CMT type 1A (CMT1A) appears to be the most prevalent form of the disease. CMT1A is associated with a submicroscopic DNA duplication spanning approximately 1.5 million bp of the short arm of chromosome 17, specifically at chromosome 17p11.2. J. Lupski et al., 66 Cell 219 (1991); P. Raemaekers et al., 1 Neuromusc. Dia. 93 (1991); P. Raemaekers et al., 29 J. Med. Genet. 5 (1992); J. Lupski et al., PCT WO 92/21694. Clinically, CMT results in a variably progressive atrophy of the distal muscles of the hands and feet. The muscular atrophy leads to an associated pes cavus foot and a claw hand deformity. The clinical signs and symptoms usually manifest themselves by the second or third decade of life, although electrophysiological abnormalities are evident much earlier. While CMT1A and HNPP are both classified as demyelinating peripheral neuropathies, their clinical and histopathological features are distinctly different.
A candidate gene for the CMT1A locus was identified when point mutations were found in the peripheral myelin protein 22 gene (Pmp-22) in mice containing the trembler (Tr) mutation and the related trembler-J (Tr.sup.J). U. Suter et al., 356 Nature 241 (1992); U. Suter et al., 89 Proc. Nat'l Acad. Sci. USA 4382 (1992). The Tr mouse is a proposed model for CMT1A because the mutation results in a hypomyelinating neuropathy, is autosomally dominant, and maps to mouse chromosome 11, which has syntenic homology with human chromosome 17p in the region of the CMT1A locus. The human PMP-22 gene maps to chromosome 17p11.2 in the duplicated region associated with CMT1A and may be the critical gene associated with CMT1A. N. Matsunami et al., 1 Nature Genet. 176 (1992); P. Patel et al., 1 Nature Genet. 157 (1992); V. Timmerman et al., 1 Nature Genet. 171 (1992); L. Valentijn et al., 1 Nature Genet. 166 (1992). Gene dosage of the PMP-22 gene has been proposed as the causal factor of CMT1A.
Present methods of diagnosing HNPP are inadequate in that they are time consuming, expensive, painful, and risky to the patient. These methods include electrophysiological methods to measure nerve conduction velocities, histochemistry to quantitate nerve fibers in nerve biopsy material, and electron microscopy to examine the ultrastructure of involved nerves.